1. Technical Field
The present disclosure relates generally to the production of acetyl salicylic acid, more commonly known as aspirin, and more particularly to apparatus and methods for converting acetic anhydride and salicylic acid to aspirin. More specifically, the disclosure relates to the reduction of mass transfer limitations in the esterification reaction to produce aspirin.
2. Background of the Invention
Acetyl salicylic acid, commonly known as aspirin, is among the most successful pharmaceutical products in the world. Medically, aspirin has been used as an analgesic and fever reducing agent, applications that continue to be recognized today. Recently research has shown that aspirin reduces the likelihood of strokes, heart attacks, and complications due to these conditions when administered after a cardiovascular incident. Furthermore, a low dose daily aspirin regimen has been demonstrated to reduce the likelihood of subsequent heart attack. As aspirin use includes minimal side effects and/or complications, aspirin is the one of most widely used pharmaceutical agents in the world. Continuing research may demonstrate further applications, such that its therapeutic uses continue to increase.
Commercially, aspirin is synthesized using a two-step process. Phenol, generally extracted from coal tar, is treated with sodium base to generate sodium phenoxide. Sodium phenoxide is then reacted with carbon dioxide under high temperature and pressure to yield salicylate, which is acidified to obtain salicylic acid. This process is known as the Kolbe-Schmitt reaction. Salicylic acid is acetylated with acetic anhydride to produce aspirin and acetic acid as byproduct.
The original U.S. patent covering the compound acetyl salicylic acid is U.S. Pat. No. 644,077, issued Feb. 27, 1900, in the name of Felix Hoffman. The Hoffman patent describes that the compound exhibits therapeutic properties. In the disclosure, a single synthetic procedure for its manufacture is taught, comprising refluxing salicylic acid and acetic anhydride for approximately two hours at 150° C.
Described in U.S. Pat. No. 671,769 is a process for producing acetylsalicylic acid by substituting the acetyl group for the hydrogen of the hydroxyl group in salicylic acid and derivatives. The reaction is effected by the reciprocal action of salicylic acid and acetic anhydride in the presence of a condensing agent. The condensing agent disclosed is concentrated sulfuric acid.
U.S. Pat. No. 3,235,583 discloses a method of synthesizing acetyl salicylic acid without the use of strong agents. The process is asserted to provide products with high purity and near theoretical yields, without using extreme or multiple recrystallization steps. The disclosed process incorporates a mixture of salicylic acid and acetic anhydride at from 40° C. to 95° C., with an approximately 20% molar excess of acetic anhydride. The mixture is reacted in a closed vacuum-equipped vessel at the elevated temperature. The process continues maintaining the elevated temperature while reducing the internal pressure. The process maintains a partial vacuum within the range of about 1.5×10−1 torr to 2.2×10−1 torr. During the reaction, it is asserted that reducing the pressure gradually to within the range of from about 3.9×10−2 torr to a minimum attainable pressure, while maintaining the elevated temperature and reduced pressure at the lower range for about 1 to 3 hours, and thereafter recovering crystalline acetyl salicylic acid from the reaction vessel. In this process, special reaction vessels are needed, pressure within the vessel must be actively controlled, and a number of hours are needed for reaction completion.
U.S. Pat. No. 3,373,187 describes a method of synthesizing aspirin by the reaction of acetic anhydride and salicylic acid using a catalytic metal salt such as Mg(OH)2. In the disclosure, reaction times of about 2 to 11 hours are presented. Typical catalytic salts mentioned as suitable for the process are magnesium hydroxide, nickel hydroxide, calcium nitrate, cobalt nitrate, and magnesium acetate. Furthermore, the concentration for the catalyst is described as between 25 ppm and 500 ppm. Large quantities of the preferred Mg(OH)2 catalyst produce significant quantities of water and Mg acetate. These products cause undesirable decomposition of the aspirin product.
U.S. Pat. No. 6,278,014 describes a process wherein CaO and/or ZnO are used in the synthesis of acetyl salicylic acid. The patent discloses the addition of calcium oxide or zinc oxide to a reaction mixture comprising stoichiometric amounts of acetic anhydride and salicylic acid. The reaction is asserted to produce aspirin having less than 2% of free salicylic acid content. Furthermore, the use of CaO or ZnO in the process eliminates the need for additional organic solvents, or recrystallization. The catalyzed process yields a dense product. In certain instances, this product may be directly mixed with common excipients. Further, the acetyl salicylic acid and excipient mixture may be compressed into tablets upon synthesis. The process forms a significant quantity of Ca acetate and/or Zn acetate.
Accordingly, there is a need in the industry for improved methods of producing acetylsalicylic acid from acetic anhydride and salicylic acid, whereby production rates are increased, unwanted reactions are reduced, and milder reaction conditions, such as lower temperature, and pressure, are commercially feasible.